Novel pharmaceutical dosage forms comprising valganciclovir hydrochloride

ABSTRACT

The present invention provides novel solid pharmaceutical dosage forms for oral administration, after being constituted in water. The solid dosage forms comprise a therapeutically effective amount of valganciclovir hydrochloride and a non-hygroscopic organic acid present in an amount sufficient to stabilize the valganciclovir hydrochloride in a predetermined amount of water. The present invention also provides novel liquid pharmaceutical dosage forms for oral administration after constituting the solid pharmaceutical dosage form with water. A non-hygroscopic bulking agent may optionally be included in the above dosage form. These novel pharmaceutical dosage forms are useful in the treatment or control of viruses such as herpes simplex virus and cytomegalovirus. The present invention also provides a method for treating these diseases employing the solid and liquid pharmaceutical dosage forms and a method for preparing these pharmaceutical dosage forms.

PRIORITY TO RELATED APPLICATIONS

This application is a continuation application of U.S. application Ser.No. 15/479,544, filed Apr. 5, 2017, which is a continuation applicationof U.S. application Ser. No. 14/529,839 (U.S. Pat. No. 9,642,911), filedOct. 31, 2014, which is a continuation application of U.S. applicationSer. No. 13/759,348, filed Feb. 5, 2013 (U.S. Pat. No. 8,889,109), whichis a continuation application of U.S. application Ser. No. 12/001,290,filed Dec. 11, 2007, which claims the benefit of U.S. ProvisionalApplication No. 60/874,634, filed Dec. 13, 2006, each of which is herebyincorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention provides novel solid pharmaceutical dosage formsfor oral administration, after being constituted in water. The soliddosage forms comprise a therapeutically effective amount ofvalganciclovir hydrochloride and a non-hygroscopic organic acid presentin an amount sufficient to stabilize the valganciclovir hydrochloride ina predetermined amount of water. The present invention also providesnovel liquid pharmaceutical dosage forms for oral administration afterconstituting the solid pharmaceutical dosage form with water. Anon-hygroscopic bulking agent may optionally be included in the abovedosage form. These novel pharmaceutical dosage forms are useful in thetreatment or control of viruses such as herpes simplex virus andcytomegalovirus. The present invention also provides a method fortreating these diseases employing the solid and liquid pharmaceuticaldosage forms and a method for preparing these pharmaceutical dosageforms.

BACKGROUND OF THE INVENTION

Valganciclovir hydrochloride is a potent antiviral agent that has beenapproved for the treatment of cytomegalovirus (CMV) retinitis inpatients with acquired immunodeficiency syndrome (AIDS) and for theprevention of CMV disease in kidney, heart, and kidney-pancreastransplantation. Valganciclovir hydrochloride is the L-monovaline esterof ganciclovir and is a stable prodrug of ganciclovir with improvedabsorption. Such characteristics are especially valuable for suppressionof herpetic infections in immunocompromised patients where oraladministration therapeutically is the preferred choice. Valganciclovirhydrochloride is described in detail in U.S. Pat. No. 6,083,953, whichdisclosure is incorporated by reference herein.

In the solid state, valganciclovir hydrochloride exhibits acceptablephysical, chemical, and light stability when stored under ambientconditions. No special storage requirements are necessary except thatexcessive humidity must be avoided. Initial attempts to formulate avalganciclovir hydrochloride pediatric preparation and a formulation forpatients who require flexibility of dosage focused on the development ofan oral liquid product. However, short-term stability data indicatedthat a liquid dosage form would be unstable for the anticipated shelflife of the product. Accordingly, there is a need for a valganciclovirhydrochloride formulation for pediatric use and for patients who requireflexibility of dosage.

SUMMARY OF THE INVENTION

The present invention provides a solid pharmaceutical dosage form fororal administration, after being constituted in water, comprising (a) atherapeutically effective amount of valganciclovir hydrochloride; and(b) a non-hygroscopic organic acid present in an amount sufficient tostabilize the valganciclovir hydrochloride in a predetermined amount ofwater.

The present invention also provides a liquid pharmaceutical dosage formfor oral administration comprising (a) a therapeutically effectiveamount of valganciclovir hydrochloride; (b) a predetermined amount ofwater; and (c) a non-hygroscopic organic acid present in an amountsufficient to stabilize the valganciclovir hydrochloride in thepredetermined amount of water.

The present invention further provides a method of treating a subjectinfected with a virus selected from the group consisting of herpessimplex virus and cytomegalovirus comprising administering to a patient,in need thereof, a therapeutically effective amount of a liquidpharmaceutical dosage form for oral administration comprising (a) atherapeutically effective amount of valganciclovir hydrochloride; (b) apredetermined amount of water; and (c) a non-hygroscopic organic acidpresent in an amount sufficient to stabilize the valganciclovirhydrochloride in the predetermined amount of water.

The present invention still further provides a method for preparing asolid pharmaceutical dosage form for oral administration, after beingconstituted in water, comprising admixing (a) a therapeuticallyeffective amount of valganciclovir hydrochloride; and (b) anon-hygroscopic organic acid present in an amount sufficient tostabilize the valganciclovir hydrochloride in a predetermined amount ofwater.

DETAILED DESCRIPTION OF THE INVENTION

Initial attempts to formulate an appropriate dosage form ofvalganciclovir hydrochloride to treat pediatric patients and patientswho require flexibility of dosage focused on the development of an oralliquid product. Short-term stability data indicated that liquid dosageforms are unstable for the anticipated shelf life of the product.Efforts therefore focused on powder dosage forms, for later constitutionwith water, to provide a reasonable shelf life for valganciclovirhydrochloride and the resulting (constituted) liquid dosage form. Toimprove the stability profile and manufacturability of the powder dosageform and the stability profile of the constituted liquid dosage form,the formulation procedure was changed from a dry mix granulation to awet mix granulation.

Because valganciclovir hydrochloride is readily soluble under acidicconditions, a solid pharmaceutical dosage form must contain an organicacid present in an amount sufficient to solubilize and stabilize thevalganciclovir hydrochloride in a predetermined amount of water for theproposed shelf life of the resulting (constituted) liquid dosage form.Hygroscopic organic acids were found to degrade the solid valganciclovirhydrochloride pharmaceutical dosage forms. Consequently, non-hygroscopicorganic acids must be used in the solid pharmaceutical dosage forms.Optionally, a bulking agent may be included in the solid pharmaceuticaldosage form to facilitate the manufacture of the solid pharmaceuticaldosage form of the present invention. Bulking agents, such ascrystalline maltose, were found to degrade the liquid (constituted)valganciclovir hydrochloride pharmaceutical dosage forms. Consequently,non-hygroscopic bulking agents, such as polyhydric alcohols in powderform, must be used in the solid pharmaceutical dosage forms.

The solid pharmaceutical dosage forms for oral administration, afterbeing constituted in water, have the advantage of being able to providethe patient with the appropriate dosage level. For example, whilevalganciclovir hydrochloride is available as a 450 mg tablet for oraladministration, liquid dosage forms may be prepared in a wide variety ofconcentration levels. A preferred liquid dosage form may be prepared at50 mg/mL to provide a wide variety of dosage levels to treat pediatricpatients and patients who require flexibility of dosage. The containerfor the liquid dosage form may be provided with a calibrated dispenserto dispense the appropriate amount of liquid containing the appropriatedosage level.

As used herein, the following terms have the given meanings:

The term “effective amount of a non-hygroscopic bulking agent” means anamount of a non-hygroscopic bulking agent sufficient to facilitate themanufacture of the solid pharmaceutical dosage form of the presentinvention. The presence of the non-hygroscopic bulking agent is optionalbut inclusion of the non-hygroscopic bulking agent makes themanufacturing process of preparing the solid pharmaceutical dosage formeasier and can provide desirable bulk and sweetness in the finalproduct.

The term “disease” specifically includes any unhealthy condition of asubject, as defined herein. Thus, “disease” herein includes any viral orrelated disease that is treatable with valganciclovir hydrochloride orpharmaceutically acceptable salts thereof.

The term “non-hygroscopic organic acid present in an amount to stabilizethe valganciclovir hydrochloride in water” means that amount ofnon-hygroscopic organic acid necessary to lower the pH of the liquidpharmaceutical dosage form of valganciclovir hydrochloride and therebystabilize the valganciclovir hydrochloride in the predetermined amountof water.

The term “pharmaceutically acceptable,” such as pharmaceuticallyacceptable carrier, excipient, etc., means pharmacologically acceptableand substantially non-toxic to the subject in the quantity at which theparticular compound is administered.

The term “pharmaceutically acceptable salt” refers to conventionalacid-addition salts or base-addition salts that retain the biologicaleffectiveness and properties of the compounds of the present inventionand are formed from suitable non-toxic organic or inorganic acids ororganic or inorganic bases. Sample acid-addition salts include thosederived from inorganic acids such as hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid andnitric acid, and those derived from organic acids such asp-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalicacid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid,and the like. Sample base-addition salts include those derived fromammonium, potassium, sodium, and quaternary ammonium hydroxides, such asfor example, tetramethylammonium hydroxide. Chemical modification of apharmaceutical compound (i.e., drug) into a salt is a technique wellknown to pharmaceutical chemists to obtain improved physical andchemical stability and solubility of compounds. See, e.g., H. Ansel et.al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6^(th) Ed.1995) at pp. 196 and 1456-1457.

The term “predetermined amount of water” means any desired amount ofwater to constitute the solid pharmaceutical dosage form of the presentinvention into a liquid pharmaceutical dosage form for oraladministration. The amount of water can vary widely depending upon thedesired concentration of the valganciclovir hydrochloride in the aqueoussolution. The desired concentration of the valganciclovir hydrochloridein the aqueous solution may depend upon such factors as the particularsubject being treated, the disease being treated, the length of time ofthe treatment, and the like.

The term “prodrug” refers to compounds which undergo transformationprior to exhibiting their pharmacological effects. The chemicalmodification of drugs to overcome pharmaceutical problems has also beentermed “drug latentiation.” Drug latentiation is the chemicalmodification of a biologically active compound to form a new compound,which upon in vivo enzymatic attack will liberate the parent compound.The chemical alterations of the parent compound are such that the changein physicochemical properties will affect the absorption, distributionand enzymatic metabolism. The definition of drug latentiation has alsobeen extended to include nonenzymatic regeneration of the parentcompound. Regeneration takes place as a consequence of hydrolytic,dissociative, and other reactions not necessarily enzyme mediated. Theterms prodrugs, latentiated drugs, and bio-reversible derivatives areused interchangeably. By inference, latentiation implies a time lagelement or time component involved in regenerating the bioactive parentmolecule in vivo. The term prodrug is general in that it includeslatentiated drug derivatives as well as those substances which areconverted after administration to the actual substance which combineswith receptors. The term prodrug is a generic term for agents whichundergo biotransformation prior to exhibiting their pharmacologicalactions. Valganciclovir hydrochloride is a prodrug of ganciclovir.

The term “subject” includes humans, non-human mammals (such as dogs,cats, rabbits, cattle, horses, sheep, goats, swine, and deer) andnon-mammals such as birds, fish and the like. Preferably the subject isa human or non-human mammal, and more preferably the subject is a human.

The term “therapeutically effective amount” with respect tovalganciclovir hydrochloride means an amount of the compound, or apharmaceutically acceptable salt thereof which, when administered to asubject in need thereof, is effective to treat, prevent, alleviate orameliorate symptoms of disease.

The term “treatment” means any treatment of a disease in a subject andincludes: (1) preventing the disease from occurring in a subject, whomay be predisposed to the disease but does not yet experience or displaysymptoms of the disease e.g., prevention of the outbreak of the clinicalsymptoms; (2) inhibiting the disease, e.g., arresting its development;or (3) relieving the disease, e.g., causing regression of the symptomsof the disease.

The present invention provides a novel solid pharmaceutical dosage formfor oral administration, after being constituted in water, comprising(a) a therapeutically effective amount of valganciclovir hydrochloride;and (b) a non-hygroscopic organic acid present in an amount sufficientto stabilize the valganciclovir hydrochloride in a predetermined amountof water.

The present invention also provides a novel liquid pharmaceutical dosageform for oral administration comprising (a) a therapeutically effectiveamount of valganciclovir hydrochloride; (b) a predetermined amount ofwater; and (c) a non-hygroscopic organic acid present in an amountsufficient to stabilize the valganciclovir hydrochloride in thepredetermined amount of water.

The present invention further provides a novel method of treating asubject infected with a virus selected from the group consisting ofherpes simplex virus and cytomegalovirus comprising administering to apatient, in need thereof, a therapeutically effective amount of a liquidpharmaceutical dosage form for oral administration comprising (a) atherapeutically effective amount of valganciclovir hydrochloride; (b) apredetermined amount of water; and (c) a non-hygroscopic organic acidpresent in an amount sufficient to stabilize the valganciclovirhydrochloride in the predetermined amount of water.

The present invention still further provides a method for preparing asolid pharmaceutical dosage form for oral administration, after beingconstituted in water, comprising admixing (a) a therapeuticallyeffective amount of valganciclovir hydrochloride; and (b) anon-hygroscopic organic acid present in an amount sufficient tostabilize the valganciclovir hydrochloride in a predetermined amount ofwater.

Valganciclovir hydrochloride (valganciclovir HCl, Valcyte®) is ahydrochloride salt of the L-valyl ester (prodrug) of ganciclovir thatexists as a mixture of two diastereomers. After oral administration,both diastereomers are rapidly converted to ganciclovir by intestinaland hepatic esterases. Ganciclovir is a synthetic analogue of2′-deoxyguanosine, which inhibits replication of human cytomegalovirusin vitro and in vivo. Ganciclovir has been approved for the treatment ofcytomegalovirus (CMV) retinitis in patients with acquiredimmunodeficiency syndrome (AIDS) and for the prevention of CMV diseasein kidney, heart, and kidney-pancreas transplantation. Valganciclovirhydrochloride is available as a 450 mg tablet for oral administration.Each tablet contains 496.3 mg of valganciclovir hydrochloride(corresponding to 450 mg of valganciclovir), and the inactiveingredients microcrystalline cellulose, povidone K-30, crospovidone andstearic acid. The film-coat applied to the tablets contains Opadry®Pink.

Valganciclovir hydrochloride is a white to off-white crystalline powderwith a molecular formula of C₁₄H₂₂N₆O₅.HCl and a molecular weight of390.83. The chemical name for valganciclovir hydrochloride is L-Valine,2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]-3-hydroxypropylester, monohydrochloride. The chemical structure of valganciclovirhydrochloride is set out below:

The solubility of valganciclovir hydrochloride (active pharmaceuticalingredient, API) in aqueous solution is pH dependent. Valganciclovirhydrochloride is a polar hydrophilic compound with a solubility of 70mg/mL in water at 25° C. at a pH of 7.0 and an n-octanol/water partitioncoefficient of 0.0095 at pH 7.0. The pKa for valganciclovirhydrochloride is 7.6. Valganciclovir hydrochloride is freely solubleunder acidic conditions with a maximum solubility of greater than 200mg/mL in the pH range of 4-6. The stability of valganciclovirhydrochloride is greatest at a pH<3.8.

Valganciclovir hydrochloride can exist in one of two crystalline forms(termed X and Y) and an amorphous form. The commercial manufacturingprocess for the valganciclovir hydrochloride produces exclusively formY. Form Y is stable with respect to the various pharmaceutical processesinvolved in the manufacture of the powder for oral solution. Allvalganciclovir hydrochloride lots used in the manufacture of formulationdevelopment, clinical, stability and registration batches were of formY. For purposes of the present invention, any polymorphic or amorphousform of valganciclovir hydrochloride may be employed since the finalformulation is liquid. Any diastereomer or mixture of diastereomers mayalso be used.

Valganciclovir hydrochloride is moderately hygroscopic, with only smallchanges in moisture observed when the valganciclovir hydrochloride isexposed to moderate relative humidity. A weight gain of up toapproximately 3% occurs when the valganciclovir hydrochloride is exposedto 80% relative humidity (for a total moisture content of up toapproximately 8%). It is reversibly hygroscopic and will either absorbor release moisture under ambient humidity conditions, depending on thewater content of the valganciclovir hydrochloride and the relativehumidity.

The therapeutically effective amount or dosage level of valgancicloviraccording to this invention can vary within wide limits. Whilevalganciclovir hydrochloride is available as a 450 mg tablet for oraladministration, solid pharmaceutical dosage forms which can beconstituted into liquid pharmaceutical dosage forms can be prepared in awide variety of concentration levels to accommodate pediatric patientsand patients who require flexibility of dosage. The container for thesolid/liquid dosage form may be provided with a calibrated dispenser todispense the appropriate amount of liquid containing the appropriatedosage level. Such dosage levels can be adjusted to the individualrequirements in each particular case regarding the patient and conditionbeing treated.

In general, the amount of valganciclovir hydrochloride present in thesolid pharmaceutical dosage form may range from about 10% to about 90%,preferably from about 25% to about 75%, more preferably from about 35%to about 60% and most preferably about 46%, by weight of the totalcomposition.

In general, the liquid pharmaceutical dosage forms, which can beconstituted from the solid pharmaceutical dosage forms using apredetermined amount of water, may be prepared at valganciclovir (asfree base) concentration levels of from about 10 mg/mL to about 90mg/mL, preferably from about 25 mg/mL to about 75 mg/mL, more preferablyfrom about 35 mg/mL to about 65 mg/mL, and most preferably about 50 mg/mL.

The non-hygroscopic organic acids in the present invention may beselected from a wide variety of non-hygroscopic organic acids. As setout above, hygroscopic organic acids degrade the solid valganciclovirhydrochloride pharmaceutical dosage forms. A non-hygroscopic organicacid will absorb less than 1% of water by weight at about 60-75%relative humidity at ambient temperatures. In one embodiment, thenon-hygroscopic organic acid is an amino acid. Preferably, the aminoacid is aspartic acid or glutamic acid. In another embodiment, thenon-hygroscopic organic acid is selected from the group consisting offumaric acid, succinic acid, adipic acid. Preferably, thenon-hygroscopic organic acid is fumaric acid or succinic acid. Morepreferably, the non-hygroscopic organic acid is fumaric acid.

The non-hygroscopic organic acid is present in an amount sufficient tostabilize the valganciclovir hydrochloride in the solid pharmaceuticaldosage form. Valganciclovir hydrochloride has a solubility of 70 mg/mLin water at 25° C. at a pH of 7.0 and is freely soluble under acidicconditions with a maximum solubility of greater than 200 mg/mL in the pHrange of 4-6. In general, the amount of non-hygroscopic organic acidwill lower the pH of the constituted valganciclovir hydrochloridesolution to a pH of <3.8, and most preferably to a pH of 3.0.

The solid pharmaceutical dosage form may optionally contain an effectiveamount of a non-hygroscopic bulking agent. As set out above, hygroscopicbulking agents degrade valganciclovir hydrochloride in solidpharmaceutical dosage forms. The presence of the non-hygroscopic bulkingagent makes the manufacturing process of preparing the solidpharmaceutical dosage form easier and can provide desirable bulk andsweetness in the final product. The non-hygroscopic bulking agent in thepresent invention may be selected from a wide variety of non-hygroscopicbulking agents. A non-hygroscopic bulking agent will absorb less than 1%of water by weight at about 60-75% relative humidity at ambienttemperatures. In general, the non-hygroscopic bulking agent is selectedfrom the group consisting of mannitol and lactose. Preferably thenon-hygroscopic bulking agent is mannitol.

The non-hygroscopic bulking agent may be present in the solidpharmaceutical dosage form in an amount from about 10% to about 90%,preferably from about 30% to about 70%, and more preferably from about40% to about 60%, by weight of the total composition.

A preferred embodiment of the present invention is set out in Table 1.The solid pharmaceutical dosage form for oral administration is apowder, which is constituted with a predetermined amount of purifiedwater, to provide a liquid pharmaceutical dosage form. The bottlecontains about 5.515 g of valganciclovir hydrochloride in a total of 12g of powder for constitution into a solution for oral administration.When constituted, the volume of the solution is 100 mL. A quantity of 1mL of the constituted solution contains 55.15 mg of valganciclovirhydrochloride corresponding to 50 mg of valganciclovir free base. Theconcentration of the valganciclovir, as free base, in the constitutedsolution is 5.0%. The valganciclovir hydrochloride and the excipientsare soluble in the aqueous vehicle. The powder blend may be manufacturedby conventional pharmaceutical processes including wet granulation. Theproduct is preferably marketed in amber glass bottles withchild-resistant plastic screw caps.

TABLE 1 Pharmaceutical Composition of Valganciclovir Hydrochloride asPowder and Constituted Solution Formulation Number F01 Unit WeightFilling Mixture Constituted Soln Components mg/120 mg g/bottle mg/mLValganciclovir HCl 55.15¹ 5.515¹ 55.15¹ Povidone K30 2.00 0.200 2.00Fumaric Acid 2.00 0.200 2.00 Sodium Benzoate 1.00 0.100 1.00 SodiumSaccharin 0.25 0.025 0.25 Mannitol 57.80 5.780 57.80 Tutti-Frutti Flavor1.80 0.180 1.80 Purified Water ² ² 0.91 mL Total 120 mg 12.000 g 1.000mL ¹Equivalent to 50 mg of valganciclovir (as free base) on dry basis(HCl salt = MW 390.83; Base = MW 354.36) ²Removed during processing

The pharmaceutical dosage forms of the present invention can be preparedaccording to the examples set out below. The examples are presented forpurposes of demonstrating, but not limiting, the preparation of thecompounds and compositions of this invention.

EXAMPLES

In accordance with the present invention, the following examples areprovided to illustrate solid and liquid pharmaceutical dosage forms.

Example 1

A comparison of valganciclovir hydrochloride formulations of Type I andType II is set out below in Table 2.

TABLE 2 Powder for Oral Solution - Comparison of Formulations Type Img/250 mg Type II (constituted = mg/120 mg 1 mL) (constituted = 1 mL)Formulation Number Ingredients J05 F01-03 F01-02 ValganciclovirHydrochloride 55.15¹ 55.15¹ 55.15¹ Citric Acid Anhydrous 9.50 — — SodiumCitrate 0.40 — — Sodium Benzoate 1.00 1.00 1.00 Fumaric Acid — 2.00 2.00Povidone K30 — 2.00 2.00 Sodium Saccharin 0.25 0.25 0.25 StrawberryFlavor #E187196 5.00 — — Tutti-Frutti Flavor #11900-31 — 1.80 1.80Maltose, Crystalline 178.70 — — Mannitol — 57.80 57.80 Purified Water —² ² Total weight per mL 250.00 mg 120.00 mg 120.00 mg Bottle Fill Weight15.00 g 14.40 g 12.00 g Amount of water to be added 51 mL 109 mL 91 mLTotal Constituted Volume 60 mL 120 mL 100 mL Bottle: Type I amber glass120 mL 120 mL 120 mL ¹Equivalent to 50 mg of valganciclovir (as freebase) on a dry basis ²Removed during processing

Type I Formulations

The following excipients were used to prepare the formulations of TypeI. Citric acid anhydrous was combined with sodium citrate to form thebuffer system to ensure an acidic pH. The acidic pH helps stabilizevalganciclovir since valganciclovir shows the greatest stability in anaqueous solution at a pH value of about 3.8 or below. Sodium benzoatewas used as a preservative agent and sodium saccharin was used as anartificial sweetening agent. Maltose, a crystalline disaccharidecarbohydrate, was used as a bulking agent (diluent) and to providedesirable mouth feel and sweetness. Strawberry flavor was used as theflavor of the oral solution.

The following procedure was used for the preparation of the Type I,Formulation J05. In step 1, sodium citrate and sodium saccharin werescreened separately and blended with a portion of the crystallinemaltose in a mixer. In step 2, the mixture from step 1 was blended withmilled citric acid anhydrous and another portion of crystalline maltose,and strawberry flavor. In step 3, the blended material was screened andblended with screened sodium benzoate and a portion of the crystallinemaltose. In step 4, the remainder of the crystalline maltose andvalganciclovir hydrochloride was blended with the blended material fromstep 2 and this blended material was then screened. The blended materialfrom step 3 was sandwiched between two layers of the screened materialfrom step 4 and mixed into the final blend. A quantity of 15 g of thefinal blend was filled into each bottle and capped with the designatedclosure.

Example 2 Type II Formulations

The reason for changing the formulation from Type I to Type II andwithin Type II was to improve the stability profile of the solidpharmaceutical dosage form and the constituted liquid pharmaceuticaldosage form for oral administration. The differences between the Type Iand the Type II formulations are set out below.

Degradation was observed in the Type I formulation and was attributed tovalganciclovir hydrochloride/citric acid interaction in the solidpharmaceutical dosage form. Citric acid is a hygroscopic organic acidand appears to degrade valganciclovir hydrochloride in the solid dosageform. Fumaric acid, a less hygroscopic organic acid, was thereforeselected to replace citric acid/sodium citrate in the Type IIformulations.

Degradation was also observed in the Type I formulation and wasattributed to valganciclovir hydrochloride/maltose interaction in theconstituted liquid pharmaceutical dosage form for oral administration.Maltose appears to degrade valganciclovir hydrochloride in the liquiddosage form. Maltose was replaced by mannitol, a polyhydric alcohol,which did not result in the degradation of valganciclovir hydrochloride.Povidone K30 (polyvinylpyrrolidone) was added as a binder and water as agranulating liquid to change the manufacturing process from a dry mix toa wet granulation process. The introduction of the wet granulationprocess considerably increased the flow properties of the fillingmixture of the Type II formulation. Tutti-Frutti flavor replacedstrawberry flavor in the proposed market formulation. The total weightof powder per bottle changed from 15.00 g, Formulation J05 (Type I), to14.40 g, Formulation F01-03 (Type II). The proposed market formulationweight, Formulation F01-02 (Type II), was then decreased to 12.00 g toallow more headspace in the bottle for shaking to effect constitution.

Example 3 Manufacturing Process for Type II Formulations

The batch manufactured for the clinical Type I formulation was initiallybased on a dry powder mixture. Upon reformulation with differentexcipients, the flow properties of the final powder mix were found to beinsufficient for appropriate performance. By using wet granulation, theflow properties of the final powder were considerably improved. Sincecommercial valganciclovir 450 mg tablets utilize an aqueous wetgranulation process with povidone K30 as the binder, this process servedas the basis for the preparation of the solid pharmaceutical dosage formfor constitution with a predetermined amount of water.

In the present process, the active substance is preblended with povidoneK30, fumaric acid, and mannitol. Sodium benzoate and sodium saccharinwere dissolved in purified water which served as the granulationsolution. The granulation is prepared in a high shear mixer. The flavoris added to the dried and milled granulates during the final blending toform the filling mixture. Development processing variables included withand without binder and its order of addition and the order of additionof sodium benzoate and sodium saccharin.

The granulation was very weak without a binder and milling produced anexcessive amount of fines. There was no difference between adding thebinder (povidone K30) as a granulating solution or adding it dry. Forprocessing ease, povidone K30 was added dry.

Sodium benzoate and sodium saccharin were added to the final milledgranulate as dry powders as well as dissolved in purified water prior tothe granulating step. Chemical analysis for sodium benzoate and itscontent uniformity showed that incorporation of the preservative intothe solution and granulating the powders with a high shear mixerresulted in a % RSD (relative standard deviation) of the preservative of<2%. Addition of dry sodium benzoate into the final powder blend createdunacceptable variability. It is critical to rinse the granulatingsolution container thoroughly with a portion of purified water to assurethe quantitative transfer of all of the sodium benzoate.

Example 4 Stability Batches

Stability data of representative lots of Type I and Type II formulationsare presented in Table 3 (as powder for constitution) and Table 4 (asconstituted solution). Type II powder and Type II constituted solutionshow a better stability profile in terms of recovery of valganciclovirand amount of total impurities.

TABLE 3 Powder for Oral Solution - Comparison of Stability DataFormulation Type I Powder Type II Powder Formulation J05 FormulationF01-02 Lot C200860 Lot P000024 Assay Assay (% Label Claim) Total (%Label Claim) Total Storage Conditions valganciclovir Impuritiesvalganciclovir Impurities Initial 100.4% 1.4% 102.1% 1.1% 12 months 25°C./60% RH 99.4% 2.0% 100.0% 1.2% 18 months 25° C./60% RH 98.9% 2.9%100.0% 1.3% 24 months 25° C./60% RH 96.9% 4.3% 101.9% 1.4%

TABLE 4 Constituted Solution - Comparison of Stability Data FormulationType I Constituted Solution Type II Constituted Solution Formulation J05Formulation F01-02 Lot C200860 Lot P000024R Assay Assay (% Label Claim)Total (% Label Claim) Total Storage Conditions valganciclovir Impuritiesvalganciclovir Impurities Initial 100.0% 1.42% 102.1% 1.1% 1 month 5° C.99.9% 1.69% 97.0% 1.1% 2 months 5° C. 99.9% 2.20% 98.1% 1.2% 3 months 5°C. Not available Not available 99.2% 1.3%

Process Optimization

Two demonstration batches of valganciclovir powder for constitution wereprepared. The first demonstration batch (series 1) was manufactured toevaluate the manufacturing process at the 5 Kg scale. This batch washand filled into bottles. No significant issues were observed during thepreparation of the batch. The second demonstration batch (series 2) wasmanufactured to evaluate the manufacturing process at the 17.25 Kgscale. The focus of the second batch was to evaluate the mechanicalbottle-filling step. The granulation, drying and blending steps for thisdemonstration batch were successfully executed. Powder filling trialsutilizing an auger filler were successful. Bottle fill weight wasmaintained at all times throughout the entire study withoutcomplications.

The valganciclovir powder manufacturing process optimization (batch size30 Kg) consisted of dry mixing, granulation solution addition, wetgranulation, wet milling, fluidized bed drying, dry milling, blendingand bottle filling. A total of 9 development batches (batch numbers 283,293, 303, 313, 323, 333, 463, 473, and 493) were manufactured atproduction scale to optimize the parameters for each manufacturing stepfor valganciclovir powder for constitution.

Manufacturing Process

Valganciclovir hydrochloride, mannitol (Parteck M200), povidone K30, andfumaric acid were placed in a high shear mixer/granulator and dry mixed.After dry mixing, the granulating solution was added to the high sheargranulator. The granulating solution consisted of sodium benzoate,sodium saccharin, and purified water and was prepared prior to the startof the dry mixing step. It is critical to transfer all of thegranulating solution to ensure 100% recovery of sodium benzoate in thefinal product. From the granulator, the wet granulation was milledthrough a Fitzmill to improve material flow and transferred to a fluidbed dryer. A comparison was made between milling and not milling the wetgranulation. From the dryer, the dried granulation was milled through aFitzmill. The granulation was then blended with premixed flavor. Acomparison was made between premixing the flavoring versus adding theflavor to the blend directly. The powder blend was then bottle filledand packaged. Material additions and transfers during the manufacturingprocess were performed via a vacuum transfer system.

The following process parameters were monitored and evaluated during thedevelopment work.

(a) dry mix granulation (blend particle size distribution);(b) wet granulation [volume of water in granulation solution, solutionaddition rate (182-558 g/min)] to a granulation endpoint (time, Kw,visual);(c) fluid bed drying, [drying endpoint(d) dry milling at a speed of 1000-4500 rpm;(e) final blending [final blend time (addition of flavor), 5-15 minutes,uniformity of dose units, active pharmaceutical ingredient andpreservative assays, sieve analysis, bulk and tapped density];(f) bottle filling (auger speed, 400-800 rpm);(g) flow determination; powder flow was assessed by evaluation ofpacking properties through bulk density determination. The Carr Index(CI) values were used to evaluate the flow of dry milled, final blendand bottle filling samples and were calculated using the followingequation;

${CI} = {\frac{{{Tap}\mspace{14mu} {Density}} - {{Bulk}\mspace{14mu} {Density}}}{{Tap}\mspace{14mu} {Density}} \times 100}$

The CI values for dry milling samples ranged from 12.66 to 39.19,indicating that the flow behavior was good to very poor. Batch #473,which had the largest amount (28%) of particles between 250-425p,possessed the best flow, while batch #323, which had the largest amount(38%) of fine particles (<75μ), possessed the worst flow among ninebatches.

Different particle size distribution profiles for dry milling wereobserved in all batches. These results are attributed to the fact thatthe granulation processes were varied in each batch (i.e., granulationsolution volume, addition time, delivery rate, feed rate, dischargerate, etc.).

Observations

Particle size distribution profiles of the final blend for batches #303and #493 were in good agreement with data from sieve analysis for thesecond demonstration batch. There were slightly more fine particles(<75μ) in batches #303 and #493 compared to the second demonstrationbatch. Water utilized in the granulation solution was in the range of2.7 to 3.45 Kg for both batches. Addition time of the granulationsolution was in the range of 4-5.5 minutes. Wet mass time was 1.5 to 2minutes. Drying endpoint (LOD) of sample port samples were in the rangeof 1.8 to 2.13%.

The CI values for final blend samples ranged from 17.44 to 33.80,indicating that the flow behavior was fair to very poor. Batches #283,#293, and #473, which contained larger amounts of 250p size particles,exhibited better flow than the batches containing larger amounts of fineparticles.

Within a batch, there was no significant difference between the flow ofstart, middle or end for the bottle filling samples of batch #283 or#293. Slight differences in flow property were observed between bothbatches. The CI values ranged from 19.10 to 24.18, indicating fair flowproperty.

Analytical Assay Results

All batches had acceptable content uniformity with % RSD (relativestandard deviation) values lower than the acceptance criteria of 5.0%.

The average analytical assay value for sodium benzoate in batch #293 was85.5%, which was within an acceptance criteria limit. Water rinsing ofthe sodium benzoate container was not performed in this batch, which mayhave resulted in a loss of sodium benzoate. Therefore, a rinsing step isnecessary to ensure complete transfer of sodium benzoate.

Batches #303 and #323 used 1.7 Kg of water to prepare the granulationsolution. Both batches produced had low levels of sodium benzoate. Thismay have resulted from an insufficient amount of water to dissolve thesodium benzoate. Therefore, a larger amount of water would be needed toensure that all of the sodium benzoate was in solution.

The blend time study for batch #333 indicated that sodium benzoate andvalganciclovir exhibited good content uniformity at all time pointsinvestigated (5, 7.5 and 10 minutes). However, blend time data for batch#493 indicated that valganciclovir had better content uniformity at 5and 10 minutes while sodium benzoate had better content uniformity at7.5 and 10 minutes. Based on these data, a blend time of 10 minutes wasselected to ensure that good content uniformity would be obtained forboth valganciclovir and sodium benzoate. The flavor premix in batch #283did not result in significant improvement in the flavor's contentuniformity in the product. Therefore, the flavor premix step would notbe included in the final process. Bottle filling was accomplished usingan All-Fill Servometer Filling machine.

Overall, physical and analytical data were acceptable for all batches.Greater weight fluctuation of the final powder blend was observed inbatch #323 when an auger speed of 600 rpm was used to fill the bottles.Therefore, an auger speed of 450 rpm was selected for the fillingprocess.

Manufacturing Process Recommendation for Registration Batches

For a dry mix procedure, mannitol (Parteck M200), povidone K30, fumaricacid powder, and valganciclovir hydrochloride were charged to a PMA 65granulator and dry mixed for 7 minutes at an impeller speed of 200±50rpm and chopper speed of 1000±50 rpm. For solution addition and wetgranulation, a total of 3.45 Kg of water (granulation solution andrinse) is required for the granulation process. The granulation solutionis to be added to the PMA 65 for 4±0.5 minutes at an impeller speed of200±50 rpm and chopper speed of 1000±50 rpm. The wet mass should bemixed for an additional 1±0.5 minutes at the same impeller and choppersettings. Wet milling is not required.

For drying, the granulation from the PMA 65 was then charged to a fluidbed dryer and dried to an LOD of 1.3 to 3.0% with a target of 2.25%. Thetarget product temperature is 50° C. (acceptable range 48°−52° C.). Formilling, the dried granules were milled through a Fitzmill at a speed of2400±50 rpm, using a #0 plate with knives forward. For blending, aflavor pre-mix is not required. The milled granules are to be blendedwith the tutti frutti flavor in a 3 cu ft tote bin blender for 10minutes at a setting of 10 rpm. An All-Fill Powder Filling Machine wasused to fill the product into the bottles with an auger speed of 450 rpmand dribble speed of 100 rpm.

A total of three registration batches (batches #024, #034 and #044) weremanufactured at production scale (30 Kg) to evaluate the parametersestablished for each manufacturing step of valganciclovir powder forconstitution. The bulk and tap densities of the final blends for batches#024, 034 and 044 were similar. All batches exhibited fair to poor flowproperties for the final blend (Carr Index values 21.79 to 31.46).

Analytical assay results for valganciclovir and sodium benzoate forbatches #024, #034 and #044 were within acceptance criteria limits.Blend uniformity ranged from 96.4% to 102.9% for valganciclovir and96.4% to 100.0% for sodium benzoate. The % RSD was in the range of 0.3to 1.2% for valganciclovir and sodium benzoate. All analytical resultsindicated acceptable content uniformity with % RSD values lower than thevalidation acceptance criteria of 5.0%.

Three registration batches of valganciclovir powder for constitutionwere successfully manufactured using process parameters established fromdevelopmental batches. All three batches met acceptance criteria limits.In-process and analytical data collected indicated that themanufacturing process is well controlled and able to provide consistentproduct quality in accordance with current GMP standards.

Efficacy of Preservative

The constituted solution contains sodium benzoate in a concentration of0.1%. This solution has satisfactory bactericidal and fungicidalpreservative effectiveness in glass bottles, which ensures thatacceptable antimicrobial efficacy will be present throughout the useperiod of the product.

Comparative Bioavailability of the Clinical Formulation Versus theMarket Formulation

The primary objective of this study was to determine the bioequivalenceof ganciclovir from the valganciclovir tutti-frutti oral solution(F01-02) and Valcyte®, the 450 mg marketed tablet formulation ofvalganciclovir hydrochloride, at a dose of 900 mg administered in thenon-fasting state. The secondary objective was to compare the systemicexposure of ganciclovir from the valganciclovir strawberry flavored oralsolution (J05) with the valganciclovir tutti-frutti flavored oralsolution (F01-02) at a dose of 900 mg.

For both AUC 0-24 (area under the curve from 0-24 hours) and Cmax(maximum peak concentration), the 90% confidence interval (CI) for themean ratios of the tablet relative to the tutti-frutti flavored oralsolution lies entirely within the acceptance region of 80% to 125% ([96,104] and [89, 101] for AUC 0-24 and Cmax, respectively). Bioequivalenceof the tablet and the tutti-frutti flavored oral solution with respectto ganciclovir plasma levels can therefore be concluded. Based on theaverage ganciclovir AUC values, the tutti-frutti flavored oral solutiondelivers similar exposures known to be safe and efficacious. Theganciclovir PK comparing the tutti frutti flavored formulation vs. thestrawberry flavored formulation is very similar in terms of Cmax and AUCresulting in 90% CI for the mean ratios of 96% to 109% and 94% to 101%,respectively.

While a number of embodiments of this invention have been represented,it is apparent that the basic construction can be altered to provideother embodiments that utilize the invention without departing from thespirit and scope of the invention. All such modifications and variationsare intended to be included within the scope of the invention as definedin the appended claims rather than the specific embodiments that havebeen presented by way of example.

1.-10. (canceled)
 11. A liquid pharmaceutical dosage form for oraladministration comprising: (a) a therapeutically effective amount ofvalganciclovir hydrochloride; (b) a predetermined amount of water; and(c) fumaric acid present in an amount sufficient to stabilize thevalganciclovir hydrochloride in the predetermined amount of water;wherein the valganciclovir hydrochloride is present in an amount ofabout 50 mg/mL. 12.-15. (canceled)
 16. The liquid dosage from accordingto claim 11, wherein the non-hygroscopic organic acid is present in theliquid dosage form in an amount sufficient to lower the pH to 3.8 orbelow.
 17. The liquid dosage form according to claim 11, furthercomprising an effective amount of a non-hygroscopic bulking agent. 18.The liquid dosage form according to claim 17, wherein thenon-hygroscopic bulking agent is selected from the group consisting ofmannitol and lactose.
 19. The liquid dosage form according to claim 18,wherein the non-hygroscopic bulking agent is mannitol.
 20. The liquiddosage form according to claim 17, wherein the non-hygroscopic bulkingagent is present in an amount up to about 90% by weight of the totalcomposition. 21.-25. (canceled)